title: DC-SIGN mediated sphingomyelinase-activation and ceramide generation is essential for enhancement of viral uptake in dendritic cells.
abstract: As pattern recognition receptor on dendritic cells (DCs), DC-SIGN binds carbohydrate structures on its pathogen ligands and essentially determines host pathogen interactions because it both skews T cell responses and enhances pathogen uptake for cis infection and/or T cell trans-infection. How these processes are initiated at the plasma membrane level is poorly understood. We now show that DC-SIGN ligation on DCs by antibodies, mannan or measles virus (MV) causes rapid activation of neutral and acid sphingomyelinases followed by accumulation of ceramides in the outer membrane leaflet. SMase activation is important in promoting DC-SIGN signaling, but also for enhancement of MV uptake into DCs. DC-SIGN-dependent SMase activation induces efficient, transient recruitment of CD150, which functions both as MV uptake receptor and microbial sensor, from an intracellular Lamp-1+ storage compartment shared with acid sphingomyelinase (ASM) within a few minutes. Subsequently, CD150 is displayed at the cell surface and co-clusters with DC-SIGN. Thus, DC-SIGN ligation initiates SMase-dependent formation of ceramide-enriched membrane microdomains which promote vertical segregation of CD150 from intracellular storage compartments along with ASM. Given the ability to promote receptor and signalosome co-segration into (or exclusion from) ceramide enriched microdomains which provide a favorable environment for membrane fusion, DC-SIGN-dependent SMase activation may be of general importance for modes and efficiency of pathogen uptake into DCs, and their routing to specific compartments, but also for modulating T cell responses.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Wuerzburg, Germany.
authors.forename: Elita
authors.initials: E
authors.lastname: Avota
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Sibylle
authors.initials: S
authors.lastname: Schneider-Schaulies
mesh_terms: D017951:Antigen Presentation; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology*; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008457:Measles; D008459:Measles virus / Q000235:genetics / Q000254:growth & development* / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013601:T-Lymphocytes / Q000821:virology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D002518:Ceramides; D037181:Lectins, C-Type; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013108:Sphingomyelin Phosphodiesterase; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C000604059:SLAMF1 protein, human